semagacestat fails to treat Alzheimer's

Yesterday, Gina Kolata in the NYT wrote that a large PHARMA is abandoning its drug semagacestat that decreases the production of amyloid in patients with Alzheimer's. IMHO I believe that this was a failed concept from the start.  Alll neurodegenerative diseases (multiple sclerosis, ALS, Huntington's, Parkinson's and many many more) occur when the central nervous system is stressed and reacts excessively. The answer for all these conditions is the same, rein in this excessive response. Treat these conditions at the source..I wrote this about Parkinson's years ago. I think PURSOR could work equally as well on other neurodegenerative disorders. It is at least worth a try.

Elsewhere, researchers at NIH have declared that mood altering drugs appear to partially protect the brain against neurodegenerative diseases  I am glad to see that mainstream medicine is coming around to this axiom.

All mood altering drugs influence the immune system (immunomodulate)

Neuroinflammation and Neurodegenerative Diseases: One Condition One Therapy

Does neuroinflammation fan the flame in neurodegenerative diseases?:

Microglial activation is the response to multiple traumatic insults whether triggered by infection, trauma or hypoxia. This common stress response can become self-feeding and can become chronic. The authors postulate that the particular presentation (PD, ALS, Huntingtons, etc) depends on genetic variation of environmental variability.

I believe and have so believed for more than a decade that all these conditions can be remitted by blocking the perpetuation of microglial activation by the use of dopamine and seotonin precursor therapy (PURSOR).

Summary

It is becoming increasingly evident that neuroinflammation plays a crucial role in the development and progression of many neurodegenerative diseases. Glia and in particular microglia are central to mediating the effects of neuroinflammation. While neuroinflammation and microglia provide an attractive therapeutic target in the treatment and prevention of neurodegenerative diseases investigators face several challenges ahead (Appendix 2) which must be overcome before one can advocate in favor of large-scale anti-inflammatory trials in the clinic. Some of these include developing approaches to improve the access of drugs to CNS tissue as well as developing therapies that maintain or optimize the beneficial effects of neuroinflammation while eliminating or minimizing its detrimental effects.

Key Observations

1. Neurodegenerative diseases are associated with signs of chronic neuroinflammation
2. A variety of initiating triggers (some as yet unknown) associated with the different neurodegenerative disorders converge at a common intersection point - activation of microglia.
3. While the initial neuroimmune response may be aimed at limiting the disease process, chronic neuroinflammation driven by persistent microglia activation is likely to aid in the progression of the disease and the hastening of neuronal demise.
4. How the inflammatory response affects specific neuronal and glial populations and contributes to specific neurodegenerative diseases remains a critical and unanswered question

Critical challenges involved in developing neuroprotective anti-inflammatory therapeutic strategies

1. Identify internal and external factors that trigger chronic neuroinflammatory responses, with a focus on how acute immune responses become chronic.
2. Identify inflammatory mediators that compromise survival of specific neuronal populations.
3. Develop therapeutic compounds that cross the blood brain barrier (BBB)
4. Selectively target destructive inflammatory mediators without compromising beneficial survival-promoting effects and overall immune function.
5. Develop inclusion and exclusion criteria for human subjects to be enrolled in clinical trials taking into account their immune status."

Does neuroinflammation fan the flame in neurodegenerative diseases and autism?

The following quotation comes from a review article that is being published this month.

"While peripheral immune access to the central nervous system (CNS) is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults. Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS. This acute neuroinflammatory response includes activation of the resident immune cells (microglia) resulting in ... the release of inflammatory mediators such as cytokines and chemokines. Chronic neuroinflammation is a long-standing and often self-perpetuating  response that persists long after an initial injury or insult. ... The sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors.

Neurodegenerative CNS disorders discussed are multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)."(REF/ FULL TEXT)

Researchers are becoming aware that  autism is another neuroinflammatory condition that can be triggered in animal experiments. Terbutaline, a bronchodilator also used to arrest preterm labor, has been associated with the development of human autism. In animal experiments, terbutaline given early, also induce a condition that appears to be like autism. Neuroinflammation, mostly associated with innate immunity, characterized by activation of microglia and astroglia, as well as increased cytokines and chemokines, has recently been documented in post mortem studies of autism brains and in the animal damaged by neuroinflammation.(REF/FULL TEXT)

Another 2009 article that reinforces the suggestion that autism and neurodegenerative diseases are central nervous system autoimmune diseases skewed towards a proinflammatory bias :

Elevated immune response in the brain of autistic patients

This study determined immune activities in the brain of ASD patients and matched normal subjects by examining cytokines in the brain tissue. Our results showed that proinflammatory cytokines (TNF-alpha, IL-6 and GM-CSF), Th1 cytokine (IFN-gamma) and chemokine (IL-8) were significantly increased in the brains of ASD patients compared with the controls. However the Th2 cytokines (IL-4, IL-5 and IL-10) showed no significant difference. The Th1/Th2 ratio was also significantly increased in ASD patients. Conclusion: ASD patients displayed an increased innate and adaptive immune response through the Th1 pathway, suggesting that localized brain inflammation and autoimmune disorder may be involved in the pathogenesis of ASD.

Finally, Paul Ashwood writes this. I would highly recommend you read the full text of his article:

Autism spectrum disorders (ASD) are part of a broad spectrum of neurodevelopmental disorders known as pervasive developmental disorders, which occur in childhood. They are characterized by impairments in social interaction, verbal and nonverbal communication and the presence of restricted and repetitive stereotyped behaviors. At the present time, the etiology of ASD is largely unknown, but genetic, environmental, immunological, and neurological factors are thought to play a role in the development of ASD. Recently, increasing research has focused on the connections between the immune system and the nervous system, including its possible role in the development of ASD. These neuroimmune interactions begin early during embryogenesis and persist throughout an individual's lifetime, with successful neurodevelopment contingent upon a normal balanced immune response. Immune aberrations consistent with a dysregulated immune response, which so far, have been reported in autistic children, include abnormal or skewed T helper cell type 1 (T(H)1)/T(H)2 cytokine profiles, decreased lymphocyte numbers, decreased T cell mitogen response, and the imbalance of serum immunoglobulin levels. In addition, autism has been linked with autoimmunity and an association with immune-based genes including human leukocyte antigen (HLA)-DRB1 and complement C4 alleles described. There is potential that such aberrant immune activity during vulnerable and critical periods of neurodevelopment could participate in the generation of neurological dysfunction characteristic of ASD.

Damage or Disruption?

The PURSOR protocol has been extremely effective in ALS. It may be that irreversible changes occur in the child with autism. However, if the changes are not permanent, neuroinflammation and the autistic behavioral abnormalities may very well be remitted with PURSOR.

Why 5-HTP and the PURSOR Protocol May Improve Parkinson's Disease Rx

Summary

The inevitable progression of Parkinson’s Disease (PD) is unresponsive to treatment. Dopamine (DA) agonists may promote the underlying neurodegenerative process. Combined 5‑hydroxytryoptophan (5-HTP), the immediate precursor of serotonin (5-HT), and levodopa therapy should block DA induced PD progression because DA and 5­­-HT have countervailing actions in the immune system. While DA promotes inflammatory Th1 cytokines, neurotoxicity and neural apoptosis (programmed cell death), 5-HT promotes anti-inflammatory Th2 cytokines, acts as a neuroprotectant, and is antiapoptotic. Combined DA and 5-HT precursor therapy (PURSOR) with levodopa and 5-HTP suspensions titrated by taste, already associated with unprecedented partial remissions in another neurodegenerative disorder, amyotrophic lateral sclerosis, should markedly improve symptomatic Parkinson’s treatment, decrease the incidence of levodopa toxicity, and, by restoring Th1/Th2 balance and putatively decreasing QUIN induced excitatory neurotoxicity, alleviate or even halt the progression of PD.

Seven Reasons:

A.      The buccal mucosal route permits both precursors to pass through the blood-brain barrier directly without first passing through the general circulation. Since this markedly diminishes the decarboxylation of either precursor prior to its entering the CNS, carbidopa is no longer necessary.
B.       Maximum therapeutic levodopa doses to assuage nigrostriatal DA deficiency should now be realized promptly and safely. Prior to the proprietary PURSOR protocol, the responsible clinician, concerned that increasing the levodopa dose could at any time induce severe adverse effects, knowing that the only clinical endpoints were the onset of levodopa toxicity or PD clinical improvement, recognizing there was no procedure to ameliorate levodopa toxicity except the passage of time, increased levodopa dosage slowly and gingerly. One can assume that many a PD patient never achieves maximal levodopa intervention because of this understandable concern. The PURSOR protocol permits one to increase levodopa more acutely since the administration of 5-HTP reverses the toxic symptoms of levodopa excess
C.      The neurotoxicity associated with PD and increased by levodopa administration presumptively can be reversed by the increase of 5-HT, a glutamate antagonist and a neuroprotectant with the ability to diminish excessive QUIN toxicity and cellular apoptosis associated with hyperstimulation.
D.      The PURSOR protocol, by promoting CNS 5-HT levels, should decrease or ablate the Th1>Th2 imbalances associated with autoimmune disorders and suppress or halt the underlying neurodegenerative PD process.
E.       The unprecedented and rapid partial remissions noted by patients with ALS treated with the PURSOR protocol strongly suggests that 5-HT is modulating the EAA-associated neurotoxicity endemic in neurodegenerative disorders.
F.      Approximately 15% of DA treated PD patients develop obsessive/compulsive disorders. The addition of 5-HT to the regimen potentially ablates this as a problem.
G.       PD destroys both dopaminergic and serotoninergic cells. If for no other reason, the joint administration of both 5-HT and DA precursors makes empiric sense.

(Full text) More Formal Presentation